Central Role of Voltage Gated Calcium Channels and Intercellular
Calcium Homeostasis in Autism

(by N. BS Lozac, first version published online
February 2007)

Introduction

Calcium is one of the most important second messenger molecules
used by living cells. Signalling carried out by calcium ions
plays an important role in many cellular processes and because
of its universal nature, disruption of calcium homeostasis under
pathological conditions can have numerous consequences.

Due to its importance, calcium homeostasis is a tightly regulated
event and many molecules and subcellular structures are involved
in maintaining its optimal levels and pathways. Calcium enters
the cell from extracellular space through plasma membrane, and
once within the cell its levels are regulated by various intercellular
stores, pumps, and buffer proteins. One way of entry into the
cell is through voltage-gated calcium channels (VGCC) on cellular
plasma membrane. Calcium entry through VGCC is an important
physiolgical event, and proper functioning of these channels
is crucial in many cellular processes. VGCC are expressed in
many diverse cells of the human body and their pharmacological
properties are independent of the cell type where they reside.

L-type calcium channels (LTCC) are voltage-gated calcium channels
that are ubiquitously expressed in the cells of the central
nervous system (CNS), the immune system and the gastrointestinal
tract, amongst others. During development LTCC are highly expressed
in the brain, and their optimal functioning is of central importance
in many aspects of embryonic and postnatal brain development,
including neuronal gene expression and differentiation, growth,
branching, migration, and structural organisation of developing
neurons. Calcium influx through these channels is directly involved
in secretion of neurotransmitters and hormones, and plays a
pivotal role in development of motor coordination and sensory
processing. Furthermore, calcium signalling is the molecular
mechanism of integration of neural circuits in the CNS, and
is able to directly moderate electrical activity and excitability.

Maintenance of calcium homeostasis is of crucial importance
in the proper functioning of the immune system and inflammatory
responses, such as responsiveness of T and B lymphocytes, differentiation
of T helper cells into Th1 and Th2 subsets and secretion of
proinflammatory cytokines. Activities of LTCC and elevations
in intracellular calcium level are the central element in the
activation of brain immune cells.

LTCC are also expressed in endothelial and smooth muscle cells
that line blood vessels, where their activities are closely
involved cerebral blood flow and maintenance of blood brain
barrier, especially in the developing brain. The same is true
of the cells lining the gastrointestinal tract, in which LTCC
and cellular levels of calcium play an important role in gut
inflammation and permeability, gut motility and gastric acid
secretion. In addition, LTCC are expressed in pancreatic beta
cells, where their activities govern many aspects of pancreatic
function, including digestive enzymes and insulin production
and secretion.

Calcium influx through LTCC plays a crucial role in mitochondrial
calcium overload and downstream mitochondrial and cellular dysfuctions,
and elevation of intracellular calcium level is responsible
for activation of ROS-generating enzymes and formation of free
radicals by the mitochondria.

Timothy syndrome is a multisystem disorder in which a mutation
in a gene that encodes Ca(V)1.2 L-type calcium channel leads
to loss of channel inactivation and subsequent intracellular
calcium overload in various cell types. Such disturbances in
calcium homoestasis are thought to underlie the multiorgan dysfunction
observed in this disorder, which includes congenital heart disease,
immune deficiency, irregular sleep patterns, hypoglycemia, cognitive
abnormalities, and autism [15454078].

Autism, or Autism Spectrum Disorders (ASD), is a group of neurodevelopmental
disorders that manifest at an early age and is characterised
by impairments in social interaction, communication, interests,
imagination and activities. Apart from neurobehavioural symptoms,
ASD individuals frequently present with impairments in areas
such as motor function and coordination, sensitivities and abnormalities
in visual and auditory processing, various gastrointestinal
symptoms, and immune dysfunction. As autism is a highly heterogenous
disorder, the symptoms can vary greatly in each affected individual.

Numerous findings in recent years point to underlying biological
abnormalities in autism, including irregularities in neurotransmitter
systems, cholesterol metabolism, mitochondrial enzyme activities,
and levels and secretion rhythms of hormones; decreased cerebral
blood flow and increased cerebral water content; elevated markers
of oxidative stress; altered intestinal microflora; and intestinal
damage and inflammation. In addition to the active, ongoing
inflammation in the gastrointestinal tract and the CNS in autism,
results of numerous studies point to an abnormality of the immune
function such as the absence of adaptive immune system/T cell
activation following stimulation, decreased NK cells activity,
dysregulated apoptosis mechanisms, imbalances of serum immunoglobulin
levels, increased numbers of monocytes, and abnormal T helper
cell ratio.

It has been suggested in the past that disturbances in calcium
signalling pathways may be the underlying molecular cause of
autism [17275285].
Furthermore, a recent postmortem study revealed significantly
elevated calcium levels in autistic brains compared
to controls, followed by elevations of mitochondrial aspartate/glutamate
carrier rates and mitochondrial metabolism and oxidation rates
(18607376).

This paper
further explores the potential role of dysfunctional calcium
homeostasis, and in particular the functional disturbances of
voltage gated calcium channels, that could lead to pathologies
of autism. Various factors that are capable of disturbing the
functioning of VGCC in critical stages of human development
are discussed. Particular attention is given to the role of
chemokine receptors as modulators of calcium signalling and
possible implications of these events in etiology of autism.

In addition, the different ways in which sex hormones influence
functioning of VGCC are proposed to be the reason for greater
prevalence of autism in males than females.